Sourcing Chemistry From Inside Humans

Small molecule drug discovery is typically a time-consuming, expensive and risky process. Empress Therapeutics is working to change this and revolutionize the field using a unique insight into the connection between genes and chemistry to identify better starting points for new medicines.

In this interview, Dr. Jason Park, co-founder and CEO of Empress Therapeutics, tells us more about the Chemilogics platform and the benefits this approach to drug discovery can offer. Park also shares Empress Therapeutics’ next steps and his thoughts on what could be in store for the future of drug discovery.

Anna MacDonald (AM): Can you tell us about the Chemilogics platform and how it can be used to create small molecule compounds?

Jason Park (JP): Chemilogics is a first-of-its-kind platform that uses the power of genetics to generate small molecule drug candidates more predictably, faster and with a higher probability of success.

Empress’s approach is simple yet ground-breaking. We started with the question: What if you could apply the power of the genetic code to discovering and making therapeutic chemistry? DNA is the code of life, providing instructions to cells to produce important molecules; DNA encodes for RNA, that encodes for proteins. But proteins are not necessarily the endpoint; some proteins catalyze the formation of chemistry.

Starting in 2017, we had the idea to use genetic data and AI to predict how groups of enzymes work together to make chemical compounds, hypothesizing that this could uncover a rich, untapped source of potential small molecule medicines within the human body.

In extending the central dogma from DNA to chemistry, Empress creates the unprecedented capability to find qualified drug-like, human-compatible chemistry with genetic associations to health and disease. We prioritize compounds most likely to translate into medicines based on proven drug-like properties, including molecular weight, potency, selectivity, and chemical and synthetic tractability. We call our approach Chemilogics because the platform creates drug products with all the versatile attributes of small molecule chemical compounds by harnessing the genetic foundation and programmability of biologics.

AM: What advantage does this approach offer over conventional drug discovery approaches?

JP: Small molecule drugs are among the most proven and valuable medicines, but the drug discovery process has remained unpredictable, time-consuming and expensive. The sequencing of the human genome unveiled new and important disease targets, but finding compounds qualified to drug those targets has largely remained a numbers game – testing or modeling ever-larger libraries of compounds to find ones with suitable drug-like and pharmacological properties.

Unlike traditional approaches that start with drug targets, Empress employs a chemistry-forward approach that puts the emphasis on starting with drug leads – compounds closer to the finish line. One advantage of sourcing chemistry from inside of humans is an increased likelihood of human compatibility, which has been borne out thus far in industry-standard safety and metabolism studies. Another is that of increased human translatability, by starting with patient data and working backwards to identify compounds associated with differences in health and disease. Empress has the potential to use its compounds to discover entirely new targets and mechanisms already selected and validated through iterative rounds of coevolution.

Our approach allows us to discover new small molecule drugs orders of magnitude faster and more predictably than conventional approaches – reducing the process from years to months, and producing compounds with a higher likelihood of success.

AM: Why has Empress chosen to initially focus on metabolites produced by commensal bacteria?

JP: We believe the power of co-evolution and genetics offers a unique advantage. Many chemical compounds important to human health, including most antibiotics and chemotherapeutics, are known to be synthesized or modified by biosynthetic proteins, especially those in microorganisms. Empress scientists realized that one of the best places to look might be in the trillions of microbes that live on and inside of humans. Because these microbes co-evolved – i.e., have been constantly evolving and adapting to their human host across the millennia and in every single human that has lived on this planet – the generation, variation and selection of chemistry has happened at a scale unimaginable to human medicinal chemists. In fact, by one calculation examining the hundreds of millions of microbial genes inside humans, we estimated a biosynthetic potential of up to 10²⁸ unique compounds.

Recent developments in metagenomic sequencing, AI/machine learning, synthetic biology and an explosion in data have finally made it possible to deploy these insights and approach at scale. Many of these innovations have been pioneered by Empress’s scientists.

AM: Empress has already identified and characterized 15 small molecule drugs. Are you able to tell us a bit more about some of these compounds and the indications they could eventually be used to treat?

JP: What I can share at this point is that our initial portfolio of drug leads spans multiple classes of targets and mechanisms, including cytokines, enzymes, G protein-coupled receptors (GPCRs) and ion channels – showing the power of the approach. These drug leads have the potential to address serious unmet medical needs in multiple indications, including immune and inflammatory, metabolic, neurologic, oncologic and pain disorders.

AM: What are the next steps for Empress?

JP: We will file multiple investigational new drug (IND) applications within the next 24 months to begin to deliver on the promise of safe, effective medicines to patients around the world with serious unmet medical needs. We are first focusing on immune and inflammatory diseases, but are actively working on cancer, metabolic diseases and other indications.

This is just the beginning. The breadth of disorders the Chemilogics platform could address is endless. The success rate and speed over the last two years in identifying promising small molecule drug candidates speaks to the platform’s ability to develop great medicines quickly.

AM: What do you see in store for the future of drug discovery?

JP: Genetic data and recombinant DNA technology launched the biotech revolution in the early 2000s. Some of our most valuable and impactful medicines are based on important large molecules, like proteins and antibodies, found inside our body. We have the potential to similarly transform the generation of small molecule drugs.

In doing so, Empress aims to bring speed and predictability to a class of medicines that comes with some highly desirable properties, including oral delivery and flexible routes of administration, more easily controlled dosing, the ability to reach disease targets inside of cells and throughout the entire body, with cost-effective manufacturing and distribution.

What we’ve heard is that people have never really seen a platform like this before, generating chemistry from genes and making promising small molecule drug leads in a fraction of the time that it normally takes. We think this is just the start of a transformation coming from the convergence of technology and the ultimate biological information molecule, DNA.

Jason Park was speaking to Anna MacDonald, Senior Science Editor for Technology Networks.

About the interviewee:

Jason Park, PhD is CEO and co-founder of Empress. He is also an operating partner of Flagship Pioneering and was a member of the founding team of Sonata Therapeutics, where he served as COO. Prior to Flagship, Jason was a core member of the Boston Consulting Group’s Health Care and Technology practices. Jason earned a PhD in biomedical engineering from Yale University, where his research culminated in the invention and clinical use of a nanoparticle drug delivery platform. He is the author of multiple patents, book chapters and more than a dozen peer-reviewed papers in scientific journals including Nature and Cell.